synaptic loss and the pathophysiology of ptsd

Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

John H. Krystal1,2,3,4, Chadi G. Abdallah1,2, Lynette A. Averill1,2, Benjamin Kelmendi1,2, Ilan Harpaz-Rotem1,2, Gerard Sanacora1,3,5, Steven M. Southwick1,2,5, and Ronald S. Duman1,2,3,5

1Department of Psychiatry, Yale University School of Medicine, 300 George St., Suite #901, New Haven, CT 06511, USA

2Clinical Neuroscience Division, VA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA

3Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

4Psychiatry Services, Yale-New Haven Hospital, New Haven, CT, USA

5Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA

Abstract

Purpose of Review—Studies of the neurobiology and treatment of PTSD have highlighted

many aspects of the pathophysiology of this disorder that might be relevant to treatment. The

purpose of this review is to highlight the potential clinical importance of an often-neglected

consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of

synaptic connectivity.

Recent Findings—Here, we will briefly review evidence that PTSD might be a “synaptic

disconnection syndrome” and highlight the importance of this perspective for the emerging

Compliance with Ethical StandardsConflict of Interest Benjamin Kelmendi declares no conflict of interest.John H. Krystal has received grants from the Department of Veterans Affairs and has received consultancy fees from Biogen, Idec, MA, Biomedisyn Corporation, Forum Pharmaceuticals, Janssen Research and Development, L.E.K. Consulting, Otsuka America Pharmaceuticals, Inc., S K Life Science, Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd., Naurex Pharmaceuticals, and Pfizer Pharmaceuticals. Dr. Krystal owns stock in ArRETT Neuroscience, Inc., Biohaven Pharmaceuticals Medical Sciences, Blackthorn Therapeutics, Inc., Luc Therapeutics, Inc., and Spring Care, Inc.Chadi G. Abdallah has received consultancy fees from Genentech and Janssen.Lynette A. Averill has received grants from the Department of Veterans Affairs and the Brain and Behavior Foundation.Ilan Harpaz-Rotem has received a grant from the Brain and Behavior Foundation.Gerard Sanacora has received consultancy fees from Allergan, Alkermes, BioHaven Pharmaceuticals Holding Company, Janssen, Merck, Sage, Taisho Pharmaceuticals, Takeda, and Vistagen Therapeutics. Dr. Sanacora has also received grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Johnson and Johnson, Hoffman La-Roche, Merck, Naurex, and Servier and has received payment from Alkermes for developing educational Disease Education non-promotional material. Dr. Sanacora owns stock in BioHaven Holding Company.Steven M. Southwick has received grants from the National Center for PSTD.Ronald S. Duman has received consultancy fees from Johnson and Johnson and Taisho and grants from Taisho, Navitor, Relmada, Allergan, Johnson and Johnson. Dr. Duman has also received honoraria payments from Johnson and Johnson and Navitor.Human and Animal Rights and Informed Consent All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/ institutional guidelines).

HHS Public AccessAuthor manuscriptCurr Psychiatry Rep. Author manuscript; available in PMC 2018 April 18.

Published in final edited form as:Curr Psychiatry Rep. ; 19(10): 74. doi:10.1007/s11920-017-0829-z.

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therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may

work, in part, by restoring synaptic connectivity.

Summary—Synaptic disconnection may contribute to the profile of PTSD symptoms that may be

targeted by novel pharmacotherapeutics.

Keywords

PTSD; Synapse; Glutamate; NMDA; Ketamine; Plasticity; Connectivity

Introduction

The field of post-traumatic stress disorder (PTSD) research has advanced significantly since

the earliest attempts to embed our understanding of this disorder within a modern

translational neuroscience context [1, 2]. So far, the greatest progress has been made in

studies related to the regulation of fear. PTSD is associated with a bias toward viewing

neutral stimuli as threat-related, increased generalization of fear, deficits in fear extinction,

and altered processing of threatening contexts that are presumed to contribute to fear-related

PTSD symptoms including anxious arousal (startle, hypervigilance), intrusive trauma-like

symptoms (intrusive thoughts, nightmares, flashbacks, emotional/ physiologic reactivity),

and avoidance of thoughts and reminders of the traumas [3–10, 11•]. These advances have

informed the evolution of cognitive and behavioral treatments for PTSD [12, 13], and have

led to the testing of pharmacologic approaches that might enhance these processes [14, 15•,

16, 17]. However, even within this area of research, it is not entirely clear why trauma-

related fear memories are often so highly resistant to extinction. For example, it is not

known whether the persistence of fear-related symptoms in PTSD reflects a deficit in

neuroplasticity and whether these neuroplasticity deficits, in turn, have an underlying

structural component.

Toward a Synaptic Deficit Hypothesis

A model of PTSD based entirely on fear conditioning may be too narrow to explain the

breadth of associated symptoms. Other PTSD symptoms listed in DSM-5 [18] may not be

consequences of dysregulated fear, such as dysphoric arousal (difficulty concentrating,

difficulty sleeping), anhedonia (loss of interest, detachment), and externalizing symptoms

(irritability/ anger, self-destructive, or reckless behavior) [3], as well as symptoms including

guilt, shame, and cognitive impairments [19•]. Some of these symptoms, such as emotional/

behavior disinhibition [20], apathy [21], and impaired attention [22] are also associated with

neural lesions that impair the functional connectivity of the brain, as might occur in the

context of traumatic brain injury or cerebrovascular disease.

The resemblance of some PTSD symptoms to symptoms associated with impaired synaptic

connectivity may be more than coincidence. It is well established that chronic stress causes

neural atrophy and decreases the number of synapses within cortical and limbic circuits

implicated in the regulation of mood, cognition, and behavior [23•]. Glutamate synapses are

the dominant form of synaptic connectivity in these circuits. As reviewed in Fig. 1, stress

compromises the integrity of signaling via glutamate synapses in several ways including by

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reducing signaling via brain-derived neurotrophic factor (BDNF) and impairing its

downstream intracellular signaling. As a consequence, there are reductions in the number of

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the

synapse, reductions in the size of dendritic spines, loss of dendritic spines supporting

synaptic connectivity, and even loss of larger dendritic elements resulting in decreased

dendritic complexity.

Factors contributing to synaptic loss in chronic stress and PTSD may include disturbances in

glucocorticoid receptor (GR) signaling, neuroinflammation, and deficits in neurotrophin

signaling [24, 25, 26•, 27, 28]. Hypothalamo-pituitary adrenal axis function in PTSD is

manifest at many levels including alterations in diurnal cortisol levels [29–31], increased GR

numbers [32] or GR function [33], and alterations in GR signaling-related proteins such as

the GR chaperone protein, FK506 binding protein 5 (FKBP5) [34•], and serum and

glucocorticoid-regulated kinase 1 (SGK1) [35•]. With so many alterations, the impact of

hypothalamo-pituitary-adrenal axis (HPA) changes may be complex, contributing to both

resilience and vulnerability. This confusion has led to the testing of both GR agonists [36,

37] and antagonists [38] as treatments for PTSD. Elevations in proinflammatory cytokines

including interleukin 1β, interleukin 6, tumor necrosis factor α, and interferon γ are

associated with PTSD [39]. One consequence of the combined hypothalamopituitary-adrenal

axis dysregulation and pro-inflammatory state may be to compromise the function of glia

responsible for maintaining synaptic glutamate homeostasis, resulting in neurotoxic

elevations of extrasynaptic glutamate levels [40].

To date, there are limited clinical data that directly support this hypothesis [34•]. One

published pilot study of postmortem tissue evaluated 500 dendritic spines from the ventral

medial frontal cortex tissue from eight PTSD cases and eight comparison subjects. They

reported that the remaining dendritic spines in PTSD tended to be immature (stubby spines

as opposed to mature mushroom spines). They also reported that elevated messenger RNA

(mRNA) levels for FKBP5, which codes for a chaperone protein for the glucocorticoid

receptor, were associated with reduced mushroom spine density.

There are neuroimaging data that indirectly support the hypothesis of deficits in synaptic

connectivity in PTSD. These findings include reductions in cortical thickness [41],

decreased subcortical volumes on MRI [42–45], reduced integrity of white matter pathways

on diffusion-weighted imaging (DTI) [46, 47], and reductions in cortical functional

connectivity in some studies [48], but more complex patterns of functional connectivity

changes in other studies [49–51]. In these studies, regional reductions in cortical volumes,

deficits in structural connectivity, and reduced functional connectivity were associated with

PTSD symptoms, cognitive impairments, and overall functional impairment, suggesting

their clinical relevance.

Synaptic loss associated with PTSD may aggravate the impact of other pathophysiologic

processes. PTSD is often comorbid with conditions that independently may contribute to

synaptic pruning including aging [52], traumatic brain injury [53], major depression [23•],

high levels of alcohol consumption [54–56], and other medical conditions. The connectivity

deficits of PTSD may exacerbate the impact of brain injury contributing to synergy in

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cortical network dysregulation, cognitive dysfunction, symptoms, and functional impairment

as well as increased PTSD rates the TBI population [57–59, 60•, 61, 62]. Similar concerns

apply to comorbid alcohol use disorders [63].

In summary, there are compelling preclinical data and early clinical correlates suggesting

that synaptic loss may be an important feature of the neuropathology of PTSD. The MRI

findings reviewed above suggest that the structural changes occur in brain regions involved

in the executive control of emotion, such as the medial prefrontal cortex; the emotional

appraisal of potentially threatening contexts, such as the anterior hippocampus; the

generation of emotional states, such as the amygdala and insula; and in the white matter

pathways connecting these regions. In computational models of circuit function, adequate

integrity of synaptic connectivity is needed to generate and maintain appropriate

representations of information [64], to support adaptive neuroplasticity [23•], and to

adaptively regulate circuits generating emotional states [65]. These functional roles for

normally dense synaptic connectivity support the hypothesis that impairments in these

functional domains might emerge from synaptic loss, contributing to PTSD symptoms.

Synaptic Deficits and Circuit Function

How might synaptic loss impair the regulation of cortical circuits? The nature of synaptic

loss described in the preclinical studies is rather subtle. Generally speaking, stress reduces

the richness of synaptic connections rather than obliterating the integrity of a brain region or

the connections between regions of the brain, as might occur in the context of traumatic

brain injury.

Computational neuroscience studies suggest that synaptic loss may impair cortical network

function in subtle and, perhaps, paradoxical ways. Stress-related synaptic loss has been best

studied in the hippocampus. Clinical studies suggest that anterior hippocampal structural

deficits in PTSD are associated to a moderate degree with reduced functional connectivity,

profiles of PTSD symptoms [44], and impaired memory [66, 67]. In animals, both chronic

stress and chronic glucocorticoid administration produce apical dendrite retraction first in

the CA3 region and then in other hippocampal regions [68]. Loss of dendritic connectivity in

both conditions is associated with reduced neuroplasticity, as reflected by the capacity to

induce long-term potentiation, and impaired memory [69–71]. The learning impairments

associated with chronic stress are also associated with altered properties of the place cells

within the hippocampus that represent spatial information. These cells become less stable

and more cue-dependent in representing spatial information [71]. This reduction in the

stability and integrity of the neural representation of information by the hippocampus is

consistent with earlier computational models of synaptic loss [72]. Together, these studies

suggest that stress-dependent synaptic loss in the hippocampus, and perhaps other regions,

may compromise cortical network functions by affecting the integrity of network functions

and by undermining neuroplasticity.

However, there are conflicting data about the precise nature of stress-related disturbances in

hippocampal network function. While some studies do not report altered neural excitability

in association hippocampal dendritic atrophy produced by chronic stress [69, 73], other

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studies report increases in neural excitability [74]. The latter have informed a computational

hippocampal network model in which dendritic atrophy produces increased excitability that

impairs neuroplasticity by saturating long-term potentiation [75]. Another study suggests

that chronic stress produces a dysfunctional dyscoordination of heightened excitability and

neuroplasticity in some neural compartments, and reduced neuroplasticity in others [76].

This work is at an early stage, and it is hoped that continued progress in computational

approaches to network alterations in PTSD will yield deeper insights into brain-behavior

relationships.

Ketamine and Synaptic Therapeutics for PTSD

One of the most important questions raised by a focus on synaptic loss in PTSD is whether

the resulting perspective informs the identification of novel therapeutics for this disorder.

One might first explore how environmental factors might influence synaptic connectivity.

Animals raised in environments without much social, sensory, or activity-related stimulation

developed reduced levels of cortical synaptic connectivity, while environmental enrichment

has the opposite effect [77–80]. For example, environmental enrichment in animals protects

animals against hippocampal dendritic atrophy and the associated memory impairment

produced by chronic stress [81]. One form of environmental enrichment that has received

particular attention is exercise. In animals, exercise has many effects that enhance

neuroplasticity, including promoting neurogenesis, increasing dendritic complexity, and

increasing synaptic connectivity ([82–84]; see Fig. 2). These effects appear to be dependent

on the level of BDNF [84]. The effects of exercise are sufficient to protect against the

detrimental stress-like effects of chronic corticosterone on neurogenesis and synaptic

connectivity [85]. Exercise appears to have beneficial effects on symptoms severity in people

with PTSD [86]. However, it is not yet clear whether these benefits are mediated by

enhancements in synaptic connectivity.

What about exercising the brain? Cognitive remediation therapies might be beneficial for

PTSD. This is a relatively new area of research. Some studies suggest that psychotherapy

may increase regional cortical volumes or white matter integrity (increased fractional

anisotropy in diffusion weighted imaging) in PTSD, but these increases are not universally

associated with clinical improvement [87•, 88, 89]. As opposed to cognitive therapies, which

aim to address aberrant thought patterns, cognitive remediation therapies are a form of

“brain exercise” that aims to engage experience-dependent neuroplasticity in order to restore

or enhance functional connectivity [90, 91]. This approach has been studied extensively in

the field of schizophrenia research [92], but it has received relatively little attention as a

treatment for PTSD symptoms.

The capacity of the brain to protect and restore synaptic connectivity in the context of

typical daily activity raises questions as to why synaptic deficits associated with stress

persist within the context of PTSD. In fact, most people do recover, at least partly, from

severe and repeated traumas. For example, the lifetime prevalence of PTSD among Vietnam

veterans was approximately 30% [93]. However, the cross-sectional rate of PTSD declined

over time to approximately 15%10 years after the Vietnam War [93] and approximately

4.5% 40 years after the war [94•]. One possibility is that synaptic deficits persist in PTSD

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because the symptoms constitute a state of chronic stress. In other words, the persisting

symptoms associated with PTSD such as fear, depression, insomnia, guilt, demoralization,

shame, and numbing may evoke complex neurobiological responses that undermine synaptic

integrity such as dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis [95],

induction of a chronic pro-inflammatory state [96], and reductions in neurotrophin signaling

[23•]. Supporting this view, as noted earlier, HPA dysregulation [25], elevations of pro-

inflammatory cytokines [27], and reductions in plasma BDNF levels [97, 98] have been

reported in people diagnosed with PTSD. Further, volume loss on MRI appears to be a

predictor of the persistence of PTSD symptoms with treatment [99, 100]. Thus, it is possible

that persisting neuroendocrine dysregulation and neuroinflammation may contribute to the

chronicity of PTSD via enhancing synaptic connectivity deficits and compromising

neuroplasticity (see Fig. 3).

Current pharmacotherapies for PTSD may work, in part, by restoring synaptic connectivity.

The most commonly prescribed agents, antidepressant medications, appear to promote

synaptic connectivity via raising BDNF levels, enhancing signaling via CREB, and

promoting synaptic growth and neurogenesis [102, 103]. Long-term treatment with

antidepressant medications appears to increase hippocampal volume and improves memory

in individuals with PTSD [104], potentially reversing the deficits described in patients [43,

105, 106]. Interpreting the effects of long-term treatments are complex. Long-term

therapeutic effects of antidepressant medications might be mediated by direct neural or anti-

inflammatory effects [107, 108] of these drugs. However, they also might reflect the long-

term effects of changes in mood or activity, as suggested by the studies of psychotherapy

effects on brain function, reviewed earlier.

The emergence of the rapid-acting antidepressants has created the opportunity to study a

treatment that might work to reduce PTSD symptoms, in part, by directly restoring synaptic

connectivity [109, 110]. The possibility of rapid antidepressant effects produced by N-

methyl-D-aspartate (NMDA) glutamate receptor antagonists was suggested by animal

models [111]. This area of research was spurred by the observation that a single dose of the

NMDA receptor antagonist, ketamine, produced pronounced antidepressant effects in the

majority of patients with treatment-resistant symptoms of depression [40, 112]. More

recently, there is preliminary evidence that ketamine produces rapid benefits in patients

diagnosed with PTSD [113]. In this study, ketamine produced improvement in PTSD

symptoms even when controlling for its antidepressant effects and in patients without

comorbid symptoms of depression.

As presented in Fig. 4, ketamine may work by rapidly enhancing synaptic connectivity and

by rapidly increasing dendritic spines in the apical dendrites of pyramidal neurons in

superficial cortical layers, reversing the effects of stress [109, 114]. The clinical evidence

supporting this hypothesis is limited currently, but it is being actively studied. In depression,

reductions in cortical functional connectivity as measured by functional MRI appear to be

ameliorated within 24 h by a single dose of ketamine, in conjunction with clinical

improvement [115•, 116]. Similar studies are underway in PTSD patients. In animals, a

single dose of ketamine causes a proliferation of functional dendritic spines. There are at

least three primary hypotheses as to how ketamine might produce these effects [23•, 40].

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One hypothesis suggests that exerts its effects by stimulating glutamate release. This

glutamate release may trigger a chain of neural effects that begins with the stimulation of

synaptic AMPA glutamate receptors and involves increased levels and release of BDNF,

stimulation of tropomyosin receptor kinase B (TrkB) receptors (the receptor for BDNF),

enhanced signaling via the Akt/molecular target of rapamycin (mTORC) signaling pathway,

increases in the synthesis of proteins associated with dendritic spines, and the rapid

emergence of new spines (see Fig. 5). Another important hypothesis is that ketamine exerts

its clinical effects by blocking extrasynaptic NMDA glutamate receptors, reducing the

phosphorylation of eukaryotic elongation factor-2 (eELF2), reducing the phosphorylation of

the associated kinase, enhancing AMPA signaling, and increasing BDNF levels [117]. A

third hypothesis, which might be viewed as a variant of the prior hypothesis, suggests that a

ketamine metabolite, 2R,6R–hydroxynorketamine, enhances AMPA signaling through a

mechanism that remains to be determined [118•]. Other hypotheses include the possibility

that antidepressant effects of ketamine are mediated by its anti-inflammatory effects [119,

120], its effects on nitric oxide signaling [121, 122], its modulation of GABA-B receptor

signaling [123], and other effects.

If ketamine proves to produce lasting improvement in PTSD, it may serve as a prototype for

other putative rapid-acting antidepressants. For example, preclinical studies suggest that

muscarinic cholinergic receptor antagonists [124], metabotropic glutamate receptor-2

antagonists [125], and AMPAkines [126] might produce rapid antidepressant effects by

directly or indirectly enhancing AMPA receptor signaling. Only the first of these

mechanisms has been tested as an antidepressant in humans, with promising early results

[127].

However, the persisting potentiation of neuroplasticity by ketamine suggests a novel role in

the treatment of PTSD: the enhancement of fear extinction among patients who have failed

to respond to exposure-based treatments. Deficits in fear extinction in PTSD are a central

challenge in treatment and modifications to traditional cognitive and behavioral therapies are

a major focus of treatment development [128, 129]. There has long been an interest in

developing medications that might enhance this process [130]. One strategy that of

enhancing NMDA receptor signaling using D-cycloserine has not proven effective in PTSD

[131]. Ketamine, perhaps by increasing synaptic connectivity, appears to increase

neuroplasticity and to enhance fear extinction in animals [132•]. This raises the possibility

that the therapeutic effects of ketamine in PTSD might be potentiated by using it to enhance

the efficacy of progressive exposure, cognitive processing therapy, eye movement

desensitization and reprocessing (EMDR), or other exposure-based therapies.

Summary and Implications

Synaptic deficits associated with PTSD may contribute to the complex profile of symptoms

and functional impairments associated with this disorder. These deficits may arise in part

from the neurobiology of chronic stress associated with persisting symptoms of PTSD. In

turn, synaptic deficits may compromise neuroplasticity and impair resilience among

individuals with PTSD, contributing to symptom chronicity and compromising clinical

responses to current treatments. A wide range of interventions could be viewed as targeting

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impaired synaptic connectivity, such as stimulating life activities, including exercise.

However, the ability to respond to these forms of self-healing may be compromised by

PTSD-related neuroplasticity deficits. Long-term antidepressant treatment may contribute to

clinical recovery by promoting synaptic plasticity. However, recent rapid-acting

antidepressants may more directly target synaptic deficits associated with PTSD and there is

now preliminary evidence of the rapid efficacy of ketamine. Further, ketamine may open a

window of increased neuroplasticity where cognitive and behavioral therapies might be

more effective in treating PTSD symptoms.

This review relies heavily on many sources of data that are quite preliminary, and so some of

its key assertions may be vulnerable to being disproved by future research. For example,

postmortem studies of brain tissue from individuals with PTSD are in their infancy. Results

from studies employing PET radiotracers that might serve to quantify cortical synaptic

density in vivo in PTSD before and after treatment have yet to be reported. Inferences about

synaptic connectivity based on MRI-based imaging methods are likely to be risky. Further,

our limited knowledge of the neurobiology of PTSD limits our ability to rigorously evaluate

the applicability of findings from animal models of stress to the pathophysiology and

treatment of this disorder. Thus, the purpose of this review is to draw attention to the

importance of synaptic loss for PTSD, balancing the focus on fear acquisition in

considerations of the pathophysiology, and treatment of PTSD, with the aim of stimulating

more research in this area.

Acknowledgments

The authors acknowledge support from the US Department of Veterans Affairs through its support for the National Center for PTSD and it support, with the US Department of Defense, of the Consortium to Alleviate PTSD. We also recognize the National Center for Advancing Translational Science for its support of the Yale Center for Clinical Investigation (UL1RR024139). In addition, the authors acknowledge the support of the US National Institute on Alcohol Abuse and Alcoholism(P50AA12870, JHK), the State of Connecticut for the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center (GS, RSD). Dr. Krystal acknowledges the following relevant financial interests. He is a co-sponsor of a patent for the intranasal administration of ketamine for the treatment of depression that was licensed by Janssen Pharmaceuticals, the maker of S-ketamine. He has a patent related to the use of riluzole to treat anxiety disorders that was licensed by Biohaven Medical Sciences. He has stock or stock options in Biohaven Medical Sciences, ARett Pharmaceuticals, Blackthorn Therapeutics, and Luc Therapeutics. He consults broadly to the pharmaceutical industry, but his annual income over the past year did not exceed $5000 for any organization. He receives over $5000 in income from the Society of Biological Psychiatry for editing the journal Biological Psychiatry. He has fiduciary responsibility for the International College of Neuropsychopharmacology as president of this organization.

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Fig. 1. Stress causes neural atrophy and synapse loss. a The influence of repeated-restraint stress (7

d) on pyramidal neurons (layer V) in the medial prefrontal cortex (mPFC) of rat. The left-

hand set of images shows that stress reduces the number and length of apical dendrites. The

right-hand set of images shows a magnified segment of dendrite, with its spines at the point

of synaptic contacts with neuronal inputs to the mPFC; repeated stress significantly

decreases the number of spine synapses. b Under normal conditions, stimulation of the

presynaptic neuron releases glutamate, resulting in the activation of postsynaptic glutamate

AMPA receptors and depolarization; this causes activation of multiple intracellular

pathways, including the BDNF-TrkB signaling pathway (and the downstream kinases Akt

and ERK) and the mTORC1 pathway. These pathways are essential for regulation of

synaptic plasticity, a fundamental adaptive learning mechanism that includes maturation

(increased spine-head diameter) and an increase in the number of synapses. This process

requires mTORC1-mediated de novo protein synthesis of synaptic proteins, including

glutamate GluA1AMPA receptors and PSD95. Repeated stress decreases BDNF and

mTORC1 signaling in part via upregulation of the negative regulator REDD1 (regulated in

DNA damage and repair), which decreases the synthesis of synaptic proteins and thereby

contributes to a decreased number of spine synapses. Other proteins that are involved in the

regulation of synaptic plasticity include GSK3 and protein phosphatase 1 (PP1) (from [23•])

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Fig. 2. Evidence that voluntary exercise increases dendritic spine density in the dentate gyrus of the

hippocampus in rats. The left figure presents the number of dendritic spines per 10 μm for

dentate granule cells. The asterisk symbol indicates p < .05. The right figure presents results

from Golgi-impregnated dentate granule cells at ×100 magnification from control (A) and

exercised (B) animals. Scale bar = 10 μM [82]

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Fig. 3. This figure illustrates a “vicious cycle” through which neuroinflammation, HPA activation,

and stress-related alterations in circuit function interact to contribute to synaptic loss and

how synaptic loss then contributes to the chronicity of PTSD by compromising the

regulation and neuroplasticity of emotion-related neural networks (modified from [101])

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Fig. 4. Confocal photomicrographs of labeled layer V pyramidal neurons in the medial prefrontal

cortex. The left figure shows the low numbers of dendritic spines present in the dendrites of

layer V pyramidal neurons after 21 days of chronic uncontrollable stress (CUS). The right

figure illustrates the reversal by a single dose of ketamine 1 day later. Red arrows highlight

dendritic spines present after ketamine

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Fig. 5. Ketamine causes a burst of glutamate that is thought to occur via disinhibition of GABA

interneurons; the tonic firing of these GABA interneurons is driven by NMDA receptors, and

the active, open-channel state allows ketamine to enter and block channel activity. The

resulting glutamate burst stimulates AMPA receptors, which causes depolarization and

activation of voltage-dependent Ca2+ channels (VDCC), leading to release of BDNF and

stimulation of TrkB receptors and activation of Akt, which then increases mTORC1

signaling, leading to the increased synthesis of proteins that are required for synapse

maturation and formation (i.e., GluA1 and PSD95). Under conditions in which BDNF

release is blocked or neutralized, or in which mTORC1 signaling is blocked by rapamycin,

the synaptic and behavioral actions of ketamine are blocked. Scopolamine also causes a

glutamate burst via blockade of acetylcholine muscarinic M1 (ACh-M1) receptors on GABA

interneurons. Antagonists ofmGluR2/3 also produce rapid antidepressant actions via

blockade of presynaptic autoreceptors that inhibit the release of glutamate. Relapse to a

depressive state is associated with a decrease of synapses on mPFC neurons, which could

occur via stress and imbalance of endocrine hormones (cortisol), estrogen, inflammatory

cytokines, and metabolic and cardiovascular illnesses (from [23•])

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synaptic loss and the pathophysiology of ptsd

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